The transforming growth factor-beta (TGF-beta or TGFβ) superfamily contains many member proteins that share common sequence elements and structural motifs. These proteins are known to elicit a wide spectrum of biological responses in a variety of cell types. Cellular signaling triggered by members of the TGFβ superfamily members involves cooperative binding of the ligand to both TGFβ Type II and Type III transmembrane receptor components, which induces assembly of an active serine/threonine kinase receptor complex with the TGFβ Type I receptor. This receptor complex initiates a signal transduction pathway by phosphorylating cytoplasmic Smad proteins, which then translocate to the nucleus and act to suppress or activate transcription of target genes.
Many TGFβ superfamily proteins have important functions during embryonic development in pattern formation and tissue specification. TGFβ superfamily protein-induced signaling regulates a variety of differentiation processes, including adipogenesis, myogenesis, chondrogenesis, hematopoiesis, and epithelial cell differentiation (for review, See Massague, 1987, Cell 49:437; Siegel et al., 2003, Nature Review Cancer, 8:807-20). In adult tissues, TGFβ superfamily proteins are also involved in processes such as tumor growth and metastasis, wound healing, bone repair, and bone remodeling. The tumor-suppressive effects of TGFβ have been demonstrated in earlier studies. See Derynck et al., 2001, Nat Genet, 29:117-129.
TGFβ antagonist molecules regulate TGFβ mediated signaling. Examples of such antagonists include monoclonal and polyclonal antibodies directed against one or more isoforms of TGFβ (U.S. Pat. No. 5,571,714 and PCT patent application WO 97/13844).
TGFβ antagonist molecules were found to inhibit breast cancer cell tumorigenicity and increase mouse spleen natural killer cell activity. See Arteaga et al., 1993, J. Clin. Invest., 92:6.
There exists a need for combination therapy modalities to treat cancer.